5,6-trimethylenepyrimidin-4-one compounds

ABSTRACT

Pyrimidone compounds of formula (I): 
                         
are inhibitors of the enzyme Lp-PLA 2  and are of use in treating atheroscelerosis.

This application is a divisional of Application Ser. No. 10/694,561filed 27, Oct. 2003 now U.S. Pat. No. 7,153,861; which is a divisionalof U.S. Ser. No. 10/357,238 filed 3, Feb. 2003 now U.S. Pat. No.6,649,619; which is a continuation of U.S. Ser. No. 09/782,930,abandoned, filed 14, Feb. 2001; which claims priority to GB 0003636.8filed 16, Feb. 2000 and GB 0101437.2 filed 19, Jan. 2001.

The present invention relates to certain novel pyrimidinone compounds,processes for their preparation, intermediates useful in theirpreparation, pharmaceutical compositions containing them and their usein therapy, in particular in the treatment of atherosclerosis.

WO 95/00649 (SmithKline Beecham plc) describe the phospholipase A2enzyme Lipoprotein Associated Phospholipase A₂ (Lp-PLA₂), the sequence,isolation and purification thereof, isolated nucleic acids encoding theenzyme, and recombinant host cells transformed with DNA encoding theenzyme. Suggested therapeutic uses for inhibitors of the enzyme includedatherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardialinfarction, reperfusion injury and acute and chronic inflammation. Asubsequent publication from the same group further describes this enzyme(Tew D et al, Arterioscler Thromb Vas Biol 1996: 16;591-9) wherein it isreferred to as LDL-PLA₂. A later patent application (WO 95/09921, IcosCorporation) and a related publication in Nature (Tjoelker et al, vol374, 6 Apr. 1995, 549) describe the enzyme PAF-AH which has essentiallythe same sequence as Lp-PLA₂ and suggest that it may have potential as atherapeutic protein for regulating pathological inflammatory events.

It has been shown that Lp-PLA₂ is responsible for the conversion ofphosphatidylcholine to lysophosphatidylcholine, during the conversion oflow density lipoprotein (LDL) to its oxidised form. The enzyme is knownto hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to givelysophosphatidylcholine and an oxidatively modified fatty acid. Bothproducts of Lp-PLA₂ action are biologically active withlysophosphatidylcholine, a component of oxidised LDL, known to be apotent chemoattractant for circulating monocytes. As such,lysophosphatidylcholine is thought play a significant role inatherosclerosis by being responsible for the accumulation of cellsloaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA₂enzyme would therefore be expected to stop the build up of thesemacrophage enriched lesions (by inhibition of the formation oflysophosphatidylcholine and oxidised free fatty acids) and so be usefulin the treatment of atherosclerosis.

A recently published study (WOSCOPS—Packard et al, N. Engl. J. Med. 343(2000) 1148-1155) has shown that the level of the enzyme Lp-PLA₂ is anindependent risk factor in coronary artery disease.

The increased lysophosphatidylcholine content of oxidatively modifiedLDL is also thought to be responsible for the endothelial dysfunctionobserved in patients with atherosclerosis. Inhibitors of Lp-PLA₂ couldtherefore prove beneficial in the treatment of this phenomenon. AnLp-PLA₂ inhibitor could also find utility in other disease states thatexhibit endothelial dysfunction including diabetes, hypertension, anginapectoris and after ischaemia and reperfusion.

In addition, Lp-PLA₂ inhibitors may also have a general application inany disorder that involves activated monocytes, macrophages orlymphocytes, as all of these cell types express Lp-PLA₂. Examples ofsuch disorders include psoriasis.

Furthermore, Lp-PLA₂ inhibitors may also have a general application inany disorder that involves lipid oxidation in conjunction with Lp-PLA₂activity to produce the two injurious products, lysophosphatidylcholineand oxidatively modified fatty acids. Such conditions include theaforementioned conditions atherosclerosis, diabetes, rheumatoidarthritis, stroke, myocardial infarction, reperfusion injury and acuteand chronic inflammation.

Patent applications WO 96/13484, WO96/19451, WO 97/02242, WO97/217675,WO97/217676, WO 97/41098, and WO97/41099 (SmithKline Beecham plc)disclose inter alia various series of 4-thionyl/sulfinyl/sulfonylazetidinone compounds which are inhibitors of the enzyme Lp-PLA₂. Theseare irreversible, acylating inhibitors (Tew et al, Biochemistry, 37,10087, 1998).

A further class of compounds has now been identified which arenon-acylating inhibitors of the enzyme Lp-PLA₂. Thus, WO 99/24420(SmithKline Beecham plc) discloses a class of pyrimidone compounds.International patent applications WO 00/10980, WO 00/66566, WO 00/66567and WO 00/68208 (SmithKline Beecham plc, published after the prioritydate of the present application) disclose other classes of pyrimidonecompounds. We have now found a further class of pyrimidone compoundswhich are distinguished by the substitution pattern at the 5 and 6position of the pyrimidone ring and which have good activity asinhibitors of the enzyme Lp-PLA₂.

Accordingly, the present invention provides a compound of formula (I):

in which:

-   -   R^(a) is hydrogen, halogen, C₍₁₋₃₎alkyl, C₍₁₋₃₎alkoxy,        hydroxyC₍₁₋₃₎alkyl, C₍₁₋₃₎alkylthio, C₍₁₋₃₎alkylsulphinyl,        aminoC₍₁₋₃₎alkyl, mono- or di-C₍₁₋₃₎alkylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkoxyC₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkylsulphonylaminoC₍₁₋₃₎alkyl, C₍₁₋₃₎alkylcarboxy, or        C₍₁₋₃₎alkylcarboxyC₍₁₋₃₎alkyl;    -   R^(b) is hydrogen, halogen, C₍₁₋₃₎alkyl, or hydroxyC₍₁₋₃₎alkyl,        with the proviso that R^(a) and R^(b) are not simultaneously        each hydrogen; or    -   R^(a) and R^(b) together are (CH₂)_(n) where n is 3 or 4, to        form, with the pyrimidine ring carbon atoms to which they are        attached a fused 5- or 6-membered carbocyclic ring; or    -   R^(a) and R^(b) together with the pyrimidine ring carbon atoms        to which they are attached form a fused benzo or heteroaryl ring        optionally substituted by 1, 2, 3 or 4 substituents which may be        the same or different selected from halogen, C₍₁₋₄₎alkyl, cyano,        C₍₁₋₄₎alkoxy or C₍₁₋₄₎alkylthio, or mono to        perfluoro-C₍₁₋₄₎alkyl);    -   R^(c) is hydrogen or C₍₁₋₃₎alkyl;    -   R² is an aryl or heteroaryl group, optionally substituted by 1,        2, 3 or 4 substituents which may be the same or different        selected from C₍₁₋₁₈₎alkyl (preferably C₍₁₋₆₎alkyl),        C₍₁₋₁₈₎alkoxy (preferably C₍₁₋₆₎alkoxy), C₍₁₋₁₈₎alkylthio        (preferably C₍₁₋₆₎alkylthio), arylC₍₁₋₁₈₎alkoxy (preferably        arylC₍₁₋₆₎alkoxy), hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶,        NR⁶COR⁷, CONR⁸R⁹, SO₂NR⁸R⁹, NR⁶SO₂R⁷, NR⁸R⁹, mono to        perfluoro-C₍₁₋₄₎alkyl, mono to perfluoro-C₍₁₋₄₎alkoxyaryl, and        arylC₍₁₋₄₎alkyl;    -   R³ is hydrogen, C₍₁₋₆₎alkyl which may be unsubstituted or        substituted by 1, 2 or 3 substituents selected from hydroxy,        halogen, OR⁶, COR⁶, carboxy, COOR⁶, CONR⁸R⁹, NR⁸R⁹, NR⁸COR⁹,        mono- or di-(hydroxyC₍₁₋₆₎alkyl)amino and        N-hydroxyC₍₁₋₆₎alkyl-N—C₍₁₋₆₎alkylamino, for instance,        1-piperidinoethyl; or    -   R³ is Het-C₍₀₋₄₎alkyl in which Het is a 5- to 7-membered        heterocyclyl ring comprising N and optionally O or S, bonded        through a carbon ling atom and in which N may be substituted by        COR⁶, COOR⁶, CONR⁸R⁹, or C₍₁₋₆₎alkyl optionally substituted by        1, 2 or 3 substituents selected from hydroxy, halogen, OR⁶,        COR⁶, carboxy, COOR⁶, CONR⁸R⁹ or NR⁸R⁹, for instance,        piperidin-4-yl, pyrrolidin-3-yl;    -   R⁴ is an aryl or a heteroaryl ring optionally substituted by 1,        2, 3 or 4 substituents which may be the same or different        selected from C₍₁₋₈₎alkyl (preferably C₍₁₋₆₎alkyl),        C₍₁₋₁₈₎alkoxy (preferably C₍₁₋₆₎alkoxy), C₍₁₋₁₈₎alkylthio        (preferably C₍₁₋₆₎alkylthio), arylC₍₁₋₁₈₎alkoxy (preferably        arylC₍₁₋₆₎alkoxy), hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶,        NR⁶COR⁷, CONR⁸R⁹, SO₂NR⁸R⁹, NR⁶SO₂R⁷, NR⁸R⁹, mono to        perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy;    -   R⁵ is an aryl or heteroaryl ring which is further optionally        substituted by 1, 2, 3 or 4 substituents which may be the same        or different selected from C₍₁₋₁₈₎alkyl (preferably        C₍₁₋₆₎alkyl), C₍₁₋₁₈₎alkoxy (preferably C₍₁₋₆₎alkoxy),        C₍₁₋₁₈₎alkylthio (preferably C₍₁₋₆₎alkylthio), arylC₍₁₋₁₈₎alkoxy        (preferably arylC₍₁₋₆₎alkoxy), hydroxy, halogen, CN, COR⁶,        carboxy, COOR⁶, CONR⁸R⁹, NR⁶COR⁷, SO₂NR⁸R⁹, NR⁶SO₂R⁷, NR⁸R⁹,        mono to perfluoro-C₍₁₋₄₎alkyl and mono to        perfluoro-C₍₁₋₄₎alkoxy;    -   R⁶ and R⁷ are independently hydrogen or C₍₁₋₂₀₎alkyl, for        instance C₍₁₋₄₎alkyl (e.g. methyl or ethyl);    -   R⁸ and R⁹ which may be the same or different is each selected        from hydrogen, C₍₁₋₁₂₎alkyl (preferably C₍₁₋₆₎alkyl); or    -   R⁸ and R⁹ together with the nitrogen to which they are attached        form a 5- to 7 membered ring optionally containing one or more        further heteroatoms selected from oxygen, nitrogen and sulphur,        and optionally substituted by one or two substituents selected        from hydroxy, oxo, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylCO, aryl, e.g.        phenyl, or aralkyl, e.g benzyl, for instance morpholine or        piperazine; or    -   R⁸ and R⁹ which may be the same or different is each selected        from CH₂R¹⁰, CHR¹¹CO₂H or a salt thereof in which:        -   R¹⁰ is COOH or a salt thereof, COOR¹², CONR⁶R⁷, CN, CH₂OH or            CH₂OR⁶;        -   R¹¹ is an amino acid side chain such as CH₂OH from serine;        -   R¹² is C₍₁₋₄₎alkyl or a pharmaceutically acceptable in vivo            hydrolysable ester group;    -   n is an integer from 1 to 4, preferably 1 or 3, more preferably        1;    -   X is O or S;    -   Y is (CH₂)_(p)(O)_(q) in which p is 1, 2 or 3 and q is 0 or p is        2 or 3 and q is 1; and    -   Z is O or a bond.

Representative examples of R^(a) include chloro, bromo, methyl, ethyl,n-propyl, methoxy, hydroxymethyl, hydroxyethyl, methylthio,methylsulphinyl, aminoethyl, dimethylaminomethyl, acetylaminoethyl,2-(methoxyacetamido)ethyl, mesylaminoethyl, ethylcarboxy,methanesulfonamidoethyl, (methoxyacetamido)ethyl andiso-propylcarboxymethyl.

Representative examples of R^(b) include hydrogen, and methyl.

Representative examples of R^(a) and R^(b) together with the pyrimidinering carbon atoms to which they are attached forming a fused benzo orheteroaryl ring ring include benzo (to give a quinazolinyl ring), pyridoand thieno, respectively.

Preferably R^(a) is methyl or ethyl and R^(b) is hydrogen or methyl, orR^(a) and R^(b) together with the pyrimidine ring carbon atoms to whichthey are attached form a fused 5- or 6-membered carbocyclic ring. Morepreferably, R^(a) and R^(b) together with the pyrimidine ring carbonatoms to which they are attached form a fused 5-membered carbocyclicring.

Representative examples of R^(c) include hydrogen and methyl.Preferably, R^(c) is hydrogen.

Preferably, X is S.

Preferably, Y is CH₂.

Preferably, Z is a direct bond.

Representative examples of R² when an aryl group include phenyl andnaphthyl. Representative examples of R² when a heteroaryl group includepyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl,benzothiazolyl, pyridazolyl and pyrazinyl.

Preferably, R² is an aryl group, optionally substituted by 1, 2, 3 or 4substituents which may be the same or different selected fromC₍₁₋₆₎alkyl, C₍₁₋₆₎alkoxy, C₍₁₋₆₎alkylthio, hydroxy, halogen, CN, monoto perfluoro-C₍₁₋₄₎alkyl, mono to perfluoro-C₍₁₋₄₎alkoxyaryl, andarylC₍₁₋₄₎alkyl. More preferably, R² is phenyl optionally substituted byhalogen, preferably from 1 to three fluorine atoms, most preferably4-fluoro.

Preferably, R²CH₂X is 4-fluorobenzylthio.

Representative examples of R³ include hydrogen, methyl,2-(ethylamino)ethyl, 2-(diethylamino)ethyl,2-(ethylamino)-2-methylpropyl, 2-(t-butylamino)ethyl, 1-piperidinoethyl,1-ethyl-piperidin-4-yl.

Preferably, R³ is C₍₁₋₃₎alkyl substituted by a substituent selected fromNR⁸R⁹; or R³ is Het-C₍₀₋₂₎alkyl in which Het is a 5- to 7-memberedheterocyclyl ring comprising N and in which N may be substituted byC₍₁₋₆₎alkyl. More preferably, R³ is 2-(diethylamino)ethyl.

Representative examples of R⁴ include phenyl, pyridine and pyrimidine.Preferably, R⁴ is phenyl.

Representative examples of R⁵ include phenyl or thienyl, optionallysubstituted by halogen or trifluoromethyl, preferably at the 4-position.Preferably, R⁵ is phenyl substituted by trifluoromethyl, preferably atthe 4-position.

Preferably, R⁴ and R⁵ together form a 4-(phenyl)phenyl,2-(phenyl)pyrimidinyl or a 2-(phenyl)pyridinyl substituent in which theremote phenyl ring may be optionally substituted by halogen ortrifluoromethyl, preferably at the 4-position. More preferably, R⁴ andR⁵ together form a 4-(4-trifluoromethylphenyl)phenyl moiety.

It will be appreciated that within the compounds of formula (I) there isa sub-group of compounds which has the formula (IA):

in which:

-   R^(a), R^(b), R^(c), n, R², R³, R⁴, R⁵, and X are as hereinbefore    defined; and

a further sub-group of compounds which has the formula (IB):

in which:

-    R^(a), R^(b), R², R³, R⁴, R⁵, and X are as hereinbefore defined, in    particular:-   R^(a) and R^(b) together with the pyrimidine ring carbon atoms to    which they are attached form a fused 5-membered carbocyclic ring;-   R²CH₂X is 4-fluorobenzylthio;-   R³ is C₍₁₋₃₎alkyl substituted by NR⁸R⁹; or-   R³ is Het-C₍₀₋₂₎alkyl in which Het is a 5- to 7-membered    heterocyclyl ring containing N and in which N may be substituted by    C₍₁₋₆₎alkyl;-   R⁴ and R⁵ form a 4-(4-trifluoromethylphenyl)phenyl moiety;-   R⁸ and R⁹ which may be the same or different is each selected from    hydrogen, or C₍₁₋₆₎alkyl); and-   X is S.

Pharmaceutically acceptable in vivo hydrolysable ester groups for R¹²include those which break down readily in the human body to leave theparent acid or its salt. Pharmaceutically acceptable in vivohydrolysable ester groups are well known in the art and examples of suchfor use in R¹² are described in WO 00/68208 (SmithKline Beecham).

It will be appreciated that when R^(c) is C₍₁₋₃₎alkyl, the carbon towhich it is attached will be a chiral centre so that diastereoisomersmay be formed. In the absence of further chiral centres, these will beenantiomers. The present invention covers all such diastereosiomers andenantiomers, including mixtures thereof.

It will be appreciated that in some instances, compounds of the presentinvention may include a basic function such as an amino group as asubstituent. Such basic functions may be used to form acid additionsalts, in particular pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts include those described by Berge, Bighley, andMonkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts may be formed frominorganic and organic acids. Representative examples thereof includemaleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic,palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, taurocholic,benzenesulfonic, p-toluenesulfonic, hydrochloric, hydrobromic, sulfuric,cyclohexylsulfamic, phosphoric and nitric acids.

It will be appreciated that in some instances, compounds of the presentinvention may include a carboxy group as a substituent. Such carboxygroups may be used to form salts, in particular pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts include thosedescribed by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66,1-19. Preferred salts include alkali metal salts such as the sodium andpotassium salts.

When used herein, the term “alkyl” and similar terms such as “alkoxy”includes all straight chain and branched isomers. Representativeexamples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.

When used herein, the term “aryl” refers to, unless otherwise defined, amono- or bicyclic aromatic ring system containing up to 10 carbon atomsin the ring system, for instance phenyl or naphthyl.

When used herein, the term “heteroaryl” refers to a mono- or bicyclicheteroaromatic ring system comprising up to four, preferably 1 or 2,heteroatoms each selected from oxygen, nitrogen and sulphur. Each ringmay have from 4 to 7, preferably 5 or 6, ring atoms. A bicyclicheteroaromatic ring system may include a carbocyclic ring.

When used herein, the terms “halogen” and “halo” include fluorine,chlorine, bromine and iodine and fluoro, chloro, bromo and iodo,respectively.

Since the compounds of the present invention, in particular compounds offormula (I), are intended for use in pharmaceutical compositions, itwill be understood that they are each provided in substantially pureform, for example at least 50% pure, more suitably at least 75% pure andpreferably at least 95% pure (% are on a wt/wt basis). Impurepreparations of the compounds of formula (I) may be used for preparingthe more pure forms used in the pharmaceutical compositions. Althoughthe purity of intermediate compounds of the present invention is lesscritical, it will be readily understood that the substantially pure formis preferred as for the compounds of formula (I). Preferably, wheneverpossible, the compounds of the present invention are obtained incrystalline form.

When some of the compounds of this invention are allowed to crystalliseor are re-crystallised from organic solvents, solvent of crystallisationmay be present in the crystalline product. This invention includeswithin its scope such solvates. Similarly, some of the compounds of thisinvention may be crystallised or re-crystallised from solventscontaining water. In such cases water of hydration may be formed. Thisinvention includes within its scope stoichiometric hydrates as well ascompounds containing variable amounts of water that may be produced byprocesses such as lyophilisation. In addition, different crystallisationconditions may lead to the formation of different polymorphic forms ofcrystalline products. This invention includes within its scope allpolymorphic forms of the compounds of formula (I).

Compounds of the present invention are inhibitors of the enzymelipoprotein associated phospholipase A₂ (Lp-PLA₂) and as such areexpected to be of use in therapy, in particular in the primary andsecondary prevention of acute coronary events, for instance those causedby atherosclerosis, including peripheral vascular atherosclerosis andcerebrovascular atherosclerosis. In a further aspect therefore thepresent invention provides a compound of formula (I) for use in therapy.

The compounds of formula (I) are inhibitors of lysophosphatidylcholineproduction by Lp-PLA₂ and may therefore also have a general applicationin any disorder that involves endothelial dysfunction, for exampleatherosclerosis, diabetes, hypertension, angina pectoris andreperfusion. In addition, compounds of formula (I) may have a generalapplication in any disorder that involves lipid oxidation in conjunctionwith enzyme activity, for example, in addition to conditions such asatherosclerosis and diabetes, other conditions such as ischaemia,rheumatoid arthritis, stroke, inflammatory conditions of the brain suchas Alzheimer's Disease, myocardial infarction, reperfusion injury,sepsis, and acute and chronic inflammation.

Further applications include any disorder that involves activatedmonocytes, macrophages or lymphocytes, as all of these cell typesexpress Lp-PLA₂. Examples of such disorders include psoriasis.

Accordingly, in a further aspect, the present invention provides for amethod of treating a disease state associated with activity of theenzyme Lp-PLA₂ which method involves treating a patient in need thereofwith a therapeutically effective amount of an inhibitor of the enzyme.The disease state may be associated with the increased involvement ofmonocytes, macrophages or lymphocytes; with the formation oflysophosphatidylcholine and oxidised free fatty acids; with lipidoxidation in conjunction with Lp-PLA₂ activity; or with endothelialdysfunction.

Compounds of the present invention may also be of use in treating theabove mentioned disease states in combination with ananti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal,anti-inflammatory, or anti-hypertension agent or an agent for loweringLp(a). Examples of the above include cholesterol synthesis inhibitorssuch as statins, anti-oxidants such as probucol, insulin sensitisers,calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.Examples of agents for lowering Lp(a) include the aminophosphonatesdescribed in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312(Symphar SA and SmithKline Beecham).

It is expected that compounds of the present invention may be used incombination with cholesterol lowering agents, for instanceco-administered with a statin. The statins are a well known class ofcholesterol lowering agents (HMG-CoA reductase inhibitors) and includeatorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin,lovastatin and ZD 4522 (also referred to as S-4522, Astra Zeneca). Thetwo agents may be administered at substantially the same time or atdifferent times, according to the discretion of the physician.

A substantial minority (approx 30%) of patients with elevated levels ofcholesterol are found to not respond to treatment with a statin. In afurther use, a compound of the present invention is administered to apatient who has failed to respond to treatment with a statin.

A further preferred combination therapy will be the use of a compound ofthe present invention and an anti-diabetic agent or an insulinsensitiser, as coronary heart disease is a major cause of death fordiabetics. Within this class, preferred compounds for use with acompound of the present invention include the PPARgamma activators, forinstance G1262570 (Glaxo Wellcome) and the glitazone class of compoundssuch as rosiglitazone (Avandia, SmithKline Beecham), troglitazone andpioglitazone.

Preferred indications include primary and secondary prevention of acutecoronary events, for instance those caused by atherosclerosis, includingperipheral vascular atherosclerosis and cerebrovascular atherosclerosis;adjunctive therapy in prevention of restenosis, and delaying theprogression of diabetic/hypertensive renal insufficiency.

In therapeutic use, the compounds of the present invention are usuallyadministered in a standard pharmaceutical composition. The presentinvention therefore provides, in a further aspect, a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier.

Suitable pharmaceutical compositions include those which are adapted fororal or parenteral administration or as a suppository. Compounds offormula (I) which are active when given orally can be formulated asliquids, for example syrups, suspensions or emulsions, tablets, capsulesand lozenges. A liquid formulation will generally consist of asuspension or solution of the compound or pharmaceutically acceptablesalt in a suitable liquid carrier(s) for example, ethanol, glycerine,non-aqueous solvent, for example polyethylene glycol, oils, or waterwith a suspending agent, preservative, flavouring or colouring agent. Acomposition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose. A composition in the form of acapsule can be prepared using routine encapsulation procedures. Forexample, pellets containing the active ingredient can be prepared usingstandard carriers and then filled into a hard gelatin capsule;alternatively, a dispersion or suspension can be prepared using anysuitable pharmaceutical carrier(s), for example aqueous gums,celluloses, silicates or oils and the dispersion or suspension thenfilled into a soft gelatin capsule. Typical parenteral compositionsconsist of a solution or suspension of the compound of formula (I) in asterile aqueous carrier or parenterally acceptable oil, for examplepolyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil orsesame oil. Alternatively, the solution can be lyophilised and thenreconstituted with a suitable solvent just prior to administration. Atypical suppository formulation comprises a compound of formula (I)which is active when administered in this way, with a binding and/orlubricating agent such as polymeric glycols, gelatins or cocoa butter orother low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet orcapsule. Each dosage unit for oral administration contains preferablyfrom 1 to 500 mg (and for parenteral administration contains preferablyfrom 0.1 to 25 mg) of a compound of the formula (I). The daily dosageregimen for an adult patient may be, for example, an oral dose ofbetween 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or anintravenous, subcutaneous, or intra-muscular dose of between 0.1 mg and100 mg, preferably between 0.1 mg and 25 mg, of the compound of theformula (I), the compound being administered 1 to 4 times per day.Suitably the compounds will be administered for a period of continuoustherapy, for example for a week or more.

A compound of formula (I) may be prepared by reacting a compound offormula (II):

in which X, n, R^(a), R^(b) and R² are as hereinbefore defined,with a compound of formula (III):R⁵ZR⁴—YR^(c)NHR³  (III)in which R^(c), R³, R⁴, R⁵, Y and Z are as hereinbefore defined; underamide forming conditions.

Amide forming conditions are well known in the art, see for instanceComprehensive Organic Synthesis 6, 382-399, and include reacting theacid compound of formula (II) and the amine compound of formula (III) inan inert solvent such as dichloromethane, at ambient temperature, in thepresence of a coupling agent. Preferred coupling agents include thosedeveloped for use in peptide chemistry, such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (“EDC”),preferably in the presence of an additive such as1-hydroxybenzotriazole, orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (“HATU”), preferably in the presence ofdi-isopropylethylamine.

Compounds of formula (I) may also be prepared by a number of otherprocesses, for instance:

(a) reacting a compound of formula (IV):

in which X, R^(a), R^(b) and R² are as hereinbefore defined,with a compound of formula (V):R⁵Z-R⁴—YR^(c)NR³—CO—(CH₂)_(n)-L¹  (V)in which n, R³, R⁴, R⁵, R^(c), Y and Z are as hereinbefore defined, andL¹ is a leaving group such as halogen, for instance bromo iodo, ortriflate;in the presence of a base such as a secondary or tertiary amine, forinstance di-isopropylethylamine, in an inert solvent such asdichloromethane;

(b) when X is S, reacting a compound of formula (VI):

in which n, R^(a), R^(b), R^(c), R³, R⁴, R⁵, Y and Z are as hereinbeforedefined, with a compound of formula (VII):R²—CH₂-L¹  (VII)in which R² and L¹ are as hereinbefore defined,in the presence of a base such as a secondary or tertiary amine, forinstance di-isopropylethylamine, in an inert solvent such asdichloromethane; or

(c) when X is O, reacting a compound of formula (VIII):

in which n, R^(a), R^(b), R^(c), R³, R⁴, R⁵, Y and Z are as hereinbeforedefined, and L² is a leaving group such as halogen or alkylthio, forinstance methylthio,with a compound of formula (IX):R²—CH₂—OH  (IX)in which R² is as hereinbefore defined,in the presence of a base such as 4-dimethylaminopyridine, in an inertsolvent such as pyridine.

It will be appreciated that an initially prepared compound of formula(I) may be converted to another compound of formula (I), by functionalgroup modification, using methods well known to those skilled in theart, for example converting a compound of formula (I) in which R^(a) isaminoalkyl to a compound of formula (I) in which R^(a) isalkylcarbonylaminoalkyl, by reaction with an acylating agent, such as,for example, acetic anhydride.

Compounds of formulae (II), (IV), (VI) and (VIII) for use in the aboveprocesses may be prepared by processes illustrated in the followingscheme I:

in which:

-   L³ is a C₍₁₋₆₎alkyl group, for instance methyl;-   R¹⁵ is a C₍₁₋₆₎alkyl group, for instance ethyl or t-butyl and-   L¹, L², R^(a), R^(b), R^(c), R², R³, R⁴, R⁵, n, X, Y and Z are as    hereinbefore defined.

With reference to Scheme I:

Amide forming conditions for step (a) are well known in the art.Preferably, the acid of formula (II) is reacted with the amine offormula (III) in an inert solvent, such as dichloromethane, at ambienttemperature and in the presence of a coupling agent such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and di-isopropylethylamine or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in thepresence of 1-hydroxybenzotriazole.

Alkylation conditions for step (b) include reaction in the presence of abase such as a secondary or tertiary amine, for instancedi-isopropylethylamine, in an inert solvent such as dichloromethene.

Conditions for step (c) include hydrolysis, for instance using aqueoussodium hydroxide in a solvent such as dioxan or, when R¹⁵ is t-butyl,dealkylation with an acid such as trifluoroacetic acid in a solvent suchas dichloromethane.

Conditions for step (d) include under thioether forming conditions.Advantageously, the reaction is carried out in the presence of a basesuch as sodium ethoxide or potassium carbonate, preferably in a solventsuch as ethanol, dimethyl formamide or acetone, or a secondary ortertiary amine base such as di-isopropylethylamine, in solvent such asdichloromethane.

In step (e), a compound of formula (XVII) is reacted with thiourea, inthe presence of sodium ethoxide (preferably generated in situ fromsodium and ethanol).

In step (f), a compound of formula (XVIII) is reacted with ethyl formatein the presence of a base such as sodium hydride or potassiumiso-propoxide.

In step (g), a compound of formula (IV) is reacted with a compound offormula (V) in the presence of a base such as a secondary or tertiaryamine, for instance di-isopropylethylamine, in an inert solvent such asdichloromethane

In step (h), a compound of formula (XIII) is reacted with a compound offormula (XIV) in a solvent such as dimethylformamide to form anintermediate thiourea, which is then treated with a base such as sodiummethoxide.

In step (i), a compound of formula (XVI) is reacted with a metalthiocyanate, for example potassium thiocyanate, in a solvent such asacetonitrile.

In step (j), a compound of formula (XVII) is reacted with a methylatingagent such as dimethyl sulphate in the presence of a base such aspotassium carbonate, followed by hydrolysis of the intermediate ester inconventional manner e.g. by basic hydrolysis using sodium hydroxide togive the corresponding carboxylic acid which may then be converted intothe acyl chloride, for instance by treatment with oxalyl chloride.

In step (k), a catalyst such as 4-dimethylaminopyridine, and in asolvent such as pyridine are used.

In step (l), a compound of formula (XIII) is reacted with a compound offormula (XV) in a solvent such as dimethylformamide to form anintermediate thiourea, which is then treated with a base such as sodiummethoxide.

In step (m) a compound of formula (XX) is converted to a compound offormula (XIX), in which R^(a) is halogen, by treatment withN-halosuccinimide, for example N-chlorosuccinimide orN-bromo-succinimide, in a solvent such as carbon tetrachloride.

Compounds of formula (II) and (IV), in particular wherein R^(a) andR^(b) together with the pyrimidine ring carbon atoms to which they areattached form a fused 5-membered carbocyclic ring, are novel and form afurther aspect of the present invention.

The present invention will now be illustrated by the following examples.

EXAMPLES

The structure and purity of the intermediates and examples was confirmedby 1H-NMR and (in nearly all cases) mass spectroscopy, even where notexplicitly indicated below.

Intermediate A1 4-(4-Chlorophenyl)benzaldehyde

(a) A mixture of 4-formylbenzeneboronic acid (2.50 g, 2 equiv),4-chloroiodobenzene (1.98 g, 1 equiv),tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.05 equiv), aqueoussodium carbonate (18 ml, 2M solution, 2 equiv) and dimethoxyethane (50ml) was stirred at reflux under argon overnight, then cooled and dilutedwith ethyl acetate. The mixture was filtered as necessary to removeinorganic residues, then the organic layer was washed successively withaqueous citric acid and brine, dried and evaporated. The crude productwas purified by chromatography (silica, 5% ethyl acetate in hexane);product fractions were evaporated to a white solid (1.32 g, 72%).

(b) A mixture of 4-chlorobenzeneboronic acid (19.4 g, 1 equiv),4-bromobenzaldehyde (22.9 g, 1 equiv), palladium(II) acetate (1.4 g,0.05 equiv) aqueous sodium carbonate (30.3 g in 144 ml solution, 2equiv) and dimethoxyethane (500 ml) was stirred at reflux under argonfor 2.5 h, then evaporated to low volume and diluted withdichloromethane. Workup continued as in (a) above to give identicalmaterial (25.2 g, 94%). ¹H-NMR (CDCl₃) δ 10.05 (1H, s), 7.96 (2H, d),7.73 (2H, d), 7.57 (2H, d), 7.46 (2H, d); MS (AP+). found (M+1)=217,C₁₃H₉ ³⁵ClO, requires 216.

Intermediate A2 N-Methyl-4-(4-chlorophenyl)benzylamine

A mixture of Intermediate A1 (3.5 g, 1 equiv), methylamine (32.3 ml of a2M solution in THF, 4 equiv) and anhydrous magnesium sulphate (4.47 g, 2equiv) was stirred at room teperature for 16 h, then filtered, the solidwashed thoroughly with ethyl acetate, and the combined filtratesevaporated to a white solid (3.7 g). This imine intermediate wassuspended in ethanol (100 ml), cooled in ice and sodium borohydride(0.61 g, 1 equiv) added portionwise. The ice bath was removed, and themixture stirred for 45 min at room temperature then at 50° C. for 1 h.The solvent was removed in vacuo, water was added to the residue, andthe product extracted into dichloromethane. Drying and evaporation ofthe solvent gave a white solid (3.56 g). ¹H-NMR (CDCl₃) δ 7.51 (4H, d),7.40 (4H, d), 3.79 (2H, s), 2.48 (3H, s); MS (APCI+). found (M+1)=232,C₁₄H₁₄ ³⁵ClN, requires 231.

Intermediate A3 N-(2-Diethylaminoethyl)-4-(4-chlorophenyl)benzylamine

A mixture of Intermediate A1 (55.0 g), N,N-diethylethylenediamine (35.6ml), 4A molecular sieve (37 g), and dichloromethane (1100 ml) wasreacted at room temperature under argon for 16 h, with occasionalagitation. The solid was filtered off and washed with dichloromethane,and the combined filtrates evaporated to a yellow foam (72.4 g). Thisintermediate imine was reduced with sodium borohydride (8.7 g) inethanol (850 ml) as described for Intermediate A2, yielding the titlecompound as a yellow oil (72.7 g). ¹H-NMR (CDCl₃) δ 1.70 (2H, t), 2.22(6H, s), 2.33 (2H, t), 2.69 (2H, br. m), 3.83 (2H, s), 7.37-7.43 (4H,m), 7.52-7.56 (4H, m).

Intermediate A4 5-Hydroxymethyl-2-(4-trifluoromethylphenyl)pyridine

A solution of Intermediate A20 (4.63 g) in dry dichloromethane (100 ml)was cooled to −78° C. under argon, then DIBAL-H (26.7 ml, 1.5M solutionin toluene) was added dropwise over 20 min. Stirring was continued for40 min at −78° C., then 2M hydrochloric acid (52 ml) was added dropwiseover 15 min. The solution was allowed to warm slowly to roomtemperature, then the organic layer was separated, washed with water,dried and evaporated. Chromatography (silica, 1:1 ethyl acetate/hexane)gave the product as a white solid (3.03 g, 75%). ¹H-NMR (CDCl₃) δ 1.85(1H, t), 4.81 (2H, d), 7.75 (2H, m), 7.83 (1H, dd), 8.11 (1H, d), 8.72(1H, m); MS (APCI+). found (M+1)=254, C₁₃H₁₀F₃NO, requires 253.

Intermediate A5 5-Formyl-2-(4-trifluoromethylphenyl)pyridine

Activated manganese dioxide (3.19 g) was added to a solution ofIntermediate A4 (0.75 g) in dichloromethane (50 ml) and stirred at roomtemperature for 16 h. The solids were filtered off and the filtrateevaporated to a pale yellow solid (0.57 g). ¹H-NMR (CDCl₃) δ 7.7 (2H,d), 7.96 (1H, d), 8.21 (2H, d), 8.27 (1H, dd), 9.17 (1H, d), 10.19 (11H,s); MS (APCI+). found (M+1)=252, C₁₃H₈F₃NO requires 251.

Intermediate A6 Ethyl 2-(4-chlorophenyl)-4-oxopyrimidine-5-carboxylate

Sodium ethoxide (11.12 ml, 2 equiv) as a 21% w/v solution in ethanol wasadded dropwise to a suspension of diethyl ethoxymalonate (3.03 ml, 1equiv) and 4-chlorobenzamidine hydrochloride (4.23 g, 1 equiv) inethanol (30 ml), then the mixture was heated to reflux for 4 hours.After cooling, the solvent was removed in vacuo and the residue wastriturated with ether. The solid was filtered off, then resuspended inwater and acidified to pH 2. The product was filtered off, washed withwater and dried; yield 2.94 g. ¹H-NMR (d₆-DMSO) δ 1.29 (3H, t), 4.26(2H, q), 7.65 (2H, m), 8.18 (2H, m) 8.65 (1H, s); MS (APCI−). found(M−1)=277/279; C₁₃H₁₁ClN₂O₃, requires 278/280.

Intermediate A7 Ethyl2-(4-chlorophenyl)-4-chloropyrimidine-5-carboxylate

Oxalyl chloride (0.31 ml, 2 equiv) was added to Intermediate A6 (0.49 g)in dichloromethane (20 ml) with ice cooling, then the mixture wasstirred for 3 hours with warming to room temperature. Evaporation of thevolatile components gave the product as a white solid (2.94 g). ¹H-NMR(CDCl₃) δ 1.44 (3H, t), 4.48 (2H, q), 7.50 (2H, m), 8.45 (2H, m), 9.17(1H, s); MS (APCI+). found (M+1)=297; C₁₃H₁₀Cl₂N₂O₂, requires 296.

Intermediate A8 Ethyl 2-(4-chlorophenyl)pyrimidine-5-carboxylate

A mixture of Intermediate A7 (6.8 g, 1 equiv), zinc powder (1.79 g, 1.2equiv), acetic acid (1.57 ml, 1.2 equiv) and THF (100 ml) was stirred at60° C. under argon for 18 hours, then a further portion of acetic acid(1 ml) and zinc (1.0 g) was added, and the reaction allowed to continuefor a further 24 hours. The solvent was removed in vacuo, the residuewas taken up in a mixture of dichloromethane and methanol, andundissolved zinc powder was removed by filtration. After evaporation ofthe solvent, the product crystallised from ethanol; yield 2.02 g. ¹H-NMR(CDCl₃) δ 1.44 (3H, t), 4.46 (2H, q), 7.48 (2H, m), 8.48 (2H, m), 9.30(2H, s); MS (APCI+). found (M+1)=263; C₁₃H₁₁ClN₂O₂, requires 262.

Intermediate A9 5-Hydroxymethyl-2-(4-trifluoromethylphenyl)pyrimidine

Intermediate A41 (0.96 g) was hydrogenated over 10% palladium oncharcoal (96 mg) in a mixture of triethylamine (2 ml) and ethanol (20ml) for 90 mins at 1 atmosphere pressure. The catalyst was removed byfilitration, the solvent was evaporated, and the residue was taken up inethyl acetate and washed successively with aq. ammonium chloride and aq.sodium bicarbonate. Drying and evaporation gave the title compound (0.77g). ¹H-NMR (CDCl₃) δ 4.82 (2H, s), 7.75 (2H, m), 8.57 (2H, m), 8.85 (2H,s); MS (APCI+). found (M+1)=255; C₁₂H₉F₃N₂O, requires 254.

Intermediate A10 3-(4-trifluoromethylphenoxy)benzyl alcohol

A mixture of 4-chlorobenzotrifluoride (27.1 g, 1.5 equiv),3-hydroxybenzyl alcohol (12.4 g, 1 equiv), copper(I) chloride (0.2 g,0.02 equiv), potassium carbonate (8.3 g, 0.6 equiv), 8-quinolinol (0.29g, 0.02 equiv) and 1,3-dimethyl-2-imidazolidinone (50 mL) was stirred at150° C. under argon for 3 days. After cooling, the residue was pouredinto water and extracted with ethyl acetate. Drying and evaporation,followed by chromatography (silica, dichloromethane) gave the titlecompound as a pale liquid (11.3 g). ¹H-NMR (CDCl₃) δ 1.88 (1H, t), 4.69(2H, d), 6.97 (1H, m), 7.04 (3H, m), 7.17 (1H, m) 7.36 (1H, m) 7.57 (2H,m); MS (APCI−). found (M−1)=267; C₁₄H₁₁F₃O₂, requires 268.

Intermediate A11 4-(4-trifluoromethylphenoxy)benzaldehyde

A mixture of 4-(trifluoromethyl)phenol (4.86 g, 1 equiv),4-fluorobenzaldehyde (3.22 mL, 1 equiv), potassium carbonate (4.15 g, 1equiv) and dimethylformamide (60 mL) was stirred at 150° C. under argonfor 3 hours, then poured into ice/water. The precipitate was filteredoff, washed with water, then extracted with hot ethanol. Undisolvedsolid was removed by filitration, and the filtrate evaporated andpurified by chromatography on silica. ¹H-NMR (CDCl₃) δ 7.14 (4H, m),7.66 (2H, m), 7.90 (2H, m), 9.97 (1H, s); MS (APCI+). found (M+1)=267;C₁₄H₉F₃O₂, requires 266.

Intermediate A12 tert-Butyl (2-hydroxyethyl)ethylcarbamate

Di-tert-butyl dicarbonate (15.5 g, 1 equiv) was added over a period of 1hour to a solution of 2-(ethylamino)ethanol (7.5 g 1 equiv) indichloromethane (30 ml) at 0° C. After stirring at room temperature for16 hours, the solvent was evaporated and the residue distilled (115° C.,0.6 mmHg) to afford the title compound as a colourless oil (13.42 g).¹H-NMR (CDCl₃) δ 1.11 (3H, t) 1.47 (9H, s), 3.27 (2H, q), 3.38 (2H, t),3.75 (2H, t).

Intermediate A13 tert-Butyl [2-(phthalimidyl)ethyl]ethylcarbamate

Diethylazodicarbonate (12.35 g, 1 equiv) was added dropwise to a mixtureof intermediate A12 (13.42 g, 1 equiv), phthalimide (10.43 g, 1 equiv)and triphenylphosphine (18.6 g, 1 equiv) in THF (200 ml) and the mixturestirred at room temperature for 16 hours. The solvent was evaporated anddiethyl ether added. The solution was cooled to 0° C. and the insolubleproducts removed by filitration. The solvent was evaporated and theresidue applied to a column (silica, 9:1 Hexane/ethyl acetate) to affordthe title compound as a colourless oil (17 g). ¹H-NMR (CDCl₃) δ 1.13(3H, m), 1.29 (9H, s), 3.26 (2H, m), 3.48 (2H, m), 3.84 (2H, t), 7.71(2H, m), 7.85 (2H, m).

Intermediate A14 tert-Butyl (2-Aminoethyl)ethylcarbamate

Hydrazine monohydrate (5.2 ml, 2 equiv) was added to a solution ofintermediate A13 (17 g, 1 equiv) in ethanol (300 ml) and the reactionstirred for 16 hours at room temperature. The resultant solid wasfiltered off and the solvent evaporated. The residue was partitionedbetween diethyl ether and sodium hydroxide (1M, 150 ml) and the organicphase dried (K₂CO₃) and the solvent removed to afford the title compoundas a yellow oil (9.05 g). ¹H-NMR (CDCl₃) δ 1.10 (3H, t), 1.45 (9H, s),2.65 (2H, q), 2.73 (2H, t), 3.23 (2H, m).

Intermediate A15 3-(4-Trifluoromethyl-biphenyl-4-yl)propan-1-ol

Borane in tetrahydrofuran (1.0M, 44.5 ml, 2.5 equiv) was added dropwiseto a solution of intermediate A23 (5.23 g, 1 equiv) in tetrahydrofuran(65 ml) at 0° C. The solution was allowed to warm to room temperatureand stirring continued for 16 hours. The reaction was quenched by theaddition of water and the mixture extracted with ethyl acetate. Theorganic phase was washed with aq. sodium bicarbonate, dried (MgSO₄) andthe solvent evaporated to afford a residue which was applied to a column(silica, dichloromethane) to afford the title compound as a colourlesssolid (4.31 g). ¹H-NMR (CDCl₃) δ 1.76 (2H, m), 2.67 (2H, t), 3.45 (2H,m), 7.32 (2H, d), 7.64 (2H, d), 7.78 (2H, d), 7.86 (2H, d).

Intermediate A16 3-(4-Trifluoromethyl-biphenyl-4-yl)propionaldehyde

Dimethylsulphoxide (2.36 ml, 2.4 equiv) was added dropwise to a solutionof oxalyl chloride (1.46 ml, 1.1 equiv) in dichloromethane (34 ml) at−55° C. and the solution stirred for 2 minutes. A solution ofintermediate A15 (4.28 g 1 equiv) in dichloromethane (40 ml) was addedslowly to the solution at −55° C. and the solution stirred for a further10 minutes prior to the addition of triethylamine (9.7 ml, 5 equiv).After stirring for a further 5 minutes the reaction was allowed to warmto room temperature and then diluted with water. The organic phase wasseparated, dried (MgSO₄) and the solvent removed to afford the titlecompound (3.48 g). ¹H-NMR (CDCl₃) δ 2.83 (2H, m), 3.02 (2H, t), 7.29(2H, d), 7.51 (2H, d), 7.67 (4H, s), 9.85 (1H, s). MS (APCI+). found(M+1)=279; C₁₆H₁₃F₃O, requires 278.

Intermediate A17 C-(4′-Trifluoromethyl-biphenyl-4-yl)methylamine

A solution of intermediate A130 (31 g, 1 equiv) in tetrahydrofuran (300ml) was added dropwise to a solution of lithium aluminium hydride (1.0Min tetrahydrofuran, 188 ml, 1.5 equiv) at room temperature withstirring. The reaction was stirred for 8 hours, after which time aq.ammonium chloride (200 ml) and then water (200 ml) was added. Theresultant mixture was filtered through celite and then extracted withdichloromethane. The organic phase was dried (MgSO₄) and solvent removedto afford the title compound (26.7 g). ¹H-NMR (DMSO) δ 3.89 (2H, s),7.52 (2H, d), 7.73 (2H, d), 7.82 (2H, d) 7.98 (2H, d).

Intermediate A18N-(1-Ethyl-piperidin-4-yl)-(4′-trifluoromethylphenyl)benzylamine

A solution of intermediate A17 (9.3 g, 1 equiv) and 1-ethyl-4-piperidone(5.0 ml, 1.05 equiv) in 1,2-dichloroethane (135 ml) was treated withsodium triacetoxyborohydride (11 g, 1.4 equiv) and acetic acid (2.23 g,1.05 equiv) at room temperature and the mixture was stirred for 24hours. The reaction was quenched by the addition of sodium hydroxide(2M, 125 ml) and extracted with diethyl ether. The organic phase wasdried (MgSO₄) and solvent evaporated to afford a residue, which wastrituated with hexane to afford the title compound as a off white solid(8.2 g). ¹H-NMR (CDCl₃) δ 1.06 (3H, t), 1.48 (3H, m), 2.01 (4H, m), 2.38(2H, q), 2.55 (1H, m), 2.92 (2H, m), 3.88 (2H, s), 7.43 (2H, d) 7.59(2H, d), 7.68 (4H, s).

Intermediate A120 tert-Butyl (2-Amino-2-methylpropyl)carbamate

Di-tert-butyl dicarbonate (6.58 g, 1 equiv) in tetrahydrofuran (100 ml)was added dropwise to a solution of 1,2-diamino-2-methylpropane (8.86 g,3.3 equiv) in tetrahydrofuran (100 ml) at 0° C. The solution was thenstirred at room temperature for 16 hours. The solvent was evaporated andthe residue partitioned between aq. sodium chloride and ethyl acetate.The organic phase was dried (K₂CO₃) was solvent evaporated to afford thetitle compound as a colourless solid (5.45 g). ¹H-NMR (CDCl₃) δ 1.09(6H, s), 1.45 (9H, s), 3.00 (2H, d). MS (APCI+). found (M+1)=189;C₉H₂₀N₂O₂, requires 188.

Intermediate A121

tert-Butyl (2-Ethylamino-2-methylpropyl)carbamate

Intermediate A120 (5.45 g, 1 equiv), iodoethane (2.32 ml, 1 equiv) andpotassium carbonate (4 g, 1 equiv) in dimethylformamide (80 ml) werestirred at room temperature for 16 hours. Solvent was evaporated and theresidue partitioned between dichloromethane and water. The organic layerwas dried (K₂CO₃), solvent evaporated and the residue applied to acolumn (silica, 10:1 dichloromethane/methanol) to afford the titlecompound as a light brown oil (3.89 g). ¹H-NMR (CDCl₃) δ 1.05 (6H, s),1.08 (3H, t), 1.45 (9H, s), 2.54 (2H, q), 3.03 (2H, m). MS (APCI+).found (M+1)=217; C₁₁H₂₄N₂O₂, requires 216.

Intermediate A122 N²-Ethyl-2-methylpropane-1,2-diamine dihydrochloride

Hydrogen chloride (4M in dioxan, 70 ml) was added to a solution ofintermediate A121 (3.89 g) in dioxan (100 ml) and the resultingsuspension stirred at room temperature for 16 hours. Solvent wasevaporated and the residue suspended in diethyl ether, the resultingsolid was filtered off and collected to afford the title compound as acolourless solid (2.99 g). ¹H-NMR (d₆-DMSO) δ 1.26 (3H, t), 1.39 (6H,s), 2.97 (2H, q), 3.19 (2H, s). MS (APCI+). found (M+1)=117; C₆H₁₆N₂,requires 116.

Intermediate A123 2-(2-tert-Butylaminoethyl)phthalimide

A mixture of 2-bromoethyl phthalimide (20 g, 2 equiv), tert-butylamine(41 ml, 1 equiv) and potassium carbonate (10.86 g, 2 equiv) indimethylformamide (200 ml) was heated to 50° C. for 48 hours. Solventwas evaporated and the residue partitioned between dichloromethane andwater. The organic phase was dried (K₂CO₃) and solvent removed to affordthe title compound as an orange solid (18.93 g). ¹H-NMR (CDCl₃), δ 1.05(9H, s), 2.85 (2H, t), 3.77 (2H, t), 7.72 (2H, m), 7.85 (2H, m)

Intermediate A124 N-tert-Butylethane-1,2-diamine

A mixture of intermediate A123 (4 g, 1 equiv) and hydrazine hydrate(1.58 ml, 2 equiv) in methylated spirit (100 ml) was heated to refluxfor 16 hours. Solid filtered off and solution used directly in the nextstep.

The following intermediates were made by the method of Intermediate A1:

No. Precursors Name A20 methyl 6-chloronicotinate, Methyl6-(4-trifluoro- 4-trifluoromethylbenzeneboronic methylphenyl)nicotinateacid A21 4-bromobenzaldehyde, 4-(4-Trifluoromethyl-4-trifluoromethylbenzeneboronic phenyl)benzaldehyde acid A224-bromoacetophenone, 4-acetyl-4′-chlorobiphenyl 4-chlorobenzeneboronicacid A23 4-(trifluoromethyl)bromobenzene 3-(4-Trifluoromethyl-4-(2-carboxyethyl)phenylboronic biphenyl-4-yl)propionic acid acid A242-(4-bromophenoxy)ethanol 2-(4-trifluoromethyl-4-trifluoromethylbenzeneboronic biphenyloxy)ethanol acid A1304-bromobenzonitrile 4′-trifluoromethyl- 4-trifluoromethylbenzeneboronicbiphenyl-4-carbonitrile acid

The following intermediates were made by the method of Intermediate A2:

No. Precursor Structure Name A25 Int. A21

N-Methyl-4-(4-trifluoromethylphenyl)benzylamine A26 Int. A5

N-methyl-2-(4-trifluoromethyl phenyl)pyrid-5-yl-methylamine

The following intermediates were made by the method of Intermediate A3:

No. Precursor Structure Name A30 Int. A21

N-(2-(diethylamino)ethyl)-4-(4-trifluoro-methylphenyl)benzylamine A31Int. A5

N-(2-(diethylamino)ethyl)-2-(4-trifluoro-methylphenyl)pyrid-5-ylmethylamineA32 Int. A50

N-(2-(diethylamino)ethyl)-2-(4-chloro-phenyl)pyrimid-5-ylmethylamine A33Int. A51

N-(2-(diethylamino)ethyl)-2-(4-trifluoro-methylphenyl)pyrimid-5-ylmethylamineA34 Int. A21

N-(2-(1-piperidino)ethyl)-4-(4-trifluoro-methylphenyl)benzylamine A35Int. A22

(±)-N-(2-(diethylamino)ethyl)-1-(4-(4-chlorophenyl)phenyl)ethylamine A36Int. A54

N-(2-(diethylamino)ethyl)-3-(4-trifluoro-methylphenoxy)benzylamine A37Int. A11

N-(2-(diethylamino)ethyl)-4-(4-trifluoro-methylphenoxy)benzylamine A38Int. A14Int. A21

tert-Butyl{2-[4-(4-trifluoromethylphenyl)-benzylamino]ethyl}ethylcarbamate A39Int. A16

N-(2-(diethylamino)ethyl)-3-(4-trifluoro-methylbiphenyl-4-yl)propylamineA140 Int. A55

N-(2-(diethylamino)ethyl)-2-(4-trifluoro-methylbiphenyl-4-yloxy)ethylamineA141 Int. A21Int. A122

N-[(2-(diethylamino)-2-ethyl)propyl]-4-(4-trifluoromethylphenyl)benzylamineA142 Int. A21Int. A124

N-tert-Butylaminoethyl-4-(4-trifluoro-methylphenyl)benzylamine

The following intermediates were made by the method of Intermediate A4:

No. Precursor Name A40 Int. A85-Hydroxymethyl-2-(4-chlorophenyl)pyrimidine A41 Int. A534-chloro-5-hydroxymethyl-2-(4- trifluoromethylphenyl)pyrimidine

The following intermediates were made by the method of Intermediate A5:

No. Precursor Name A50 Int. A40 5-Formyl-2-(4-chlorophenyl)pyrimidineA51 Int. A9 5-Formyl-2-(4-trifluoromethylphenyl)pyrimidine A54 Int. A103-(4-trifluoromethylphenoxy)benzaldehyde

The following intermediate was made by the method of Intermediate A6:

No. Precursors Name A52 diethyl ethoxymalonate, Ethyl2-(4-trifluoromethyl- 4-trifluoromethylbenzamidine•HClphenyl)-4-oxopyrimidine-5- carboxylate

The following intermediate was made by the method of Intermediate A7:

No. Precursor Name A53 Int. A52 Ethyl2-(4-trifluoromethylphenyl)-4-chloropyrimidine- 5-carboxylate

The following intermediate was made by the method of Intermediate A16:

No. Precursor Name A55 Int. A24(4-trifluoromethylbiphenyl-4-yloxy)acetaldehyde

The following intermediates were made by the method of Intermediate A18,using Intermediate A17 and the appropriately substituted1-alkyl-4-piperidone:

No. Name A60 N-(1-methylpiperidin-4-yl)-(4′-trifluoromethylphenyl)benzylamine A61 N-(1-isopropylpiperidin-4-yl)-(4′-trifluoromethylphenyl)benzylamine A62N-(1-(2-methoxyethyl)piperidin-4-yl)-(4′-trifluoromethylphenyl)benzylamine

The following compounds are commercially available:

-   Intermediate B1, 2-thiouracil; Intermediate B2,    5-methyl-2-thiouracil; Intermediate B3, 5-ethyl-2-thiouracil;    Intermediate B4, 5-propyl-2-thiouracil; Intermediate B5,    5,6-dimethyl-2-thiouracil;

The following compounds are available by literature methods:

-   Intermediate B6, 5-carbethoxy-2-thiouracil (J. Amer. Chem. Soc. 794,    64 (1942));-   Intermediate B7, 5,6-trimethylene-2-thiouracil (J. Amer. Chem. Soc.    3108, 81 (1959));-   Intermediate B8, 5,6-tetramethylene-2-thiouracil (J. Org. Chem. 133,    18 (1953));-   Intermediate B9, 5-methoxy-2-thiouracil (J. Chem. Soc. 4590 (1960)).

Intermediate B10 5-(2-hydroxyethyl)-2-thiouracil

A solution of ethyl formate (33.1 ml, 2.1 equiv) and γ-butyrolactone (15ml, 1 equiv) in ether (400 ml) was added dropwise with stirring to asolution of potassium t-butoxide (52.5 g, 2.4 equiv) in tetrahydrofuran(400 ml). The mixture was allowed to warm to room temperature, andstirred overnight. The solvent was removed in vacuo, 2-propanol (600 ml)and thiourea (29.7 g, 2 equiv) were added, and the mixture was heated toreflux for 5 h. After cooling to room temperature, the precipitate wasfiltered off, dissolved in water (500 ml), and washed twice with ether.The aqueous solution was acidified to pH 5.5 with acetic acid, and theresulting precipitate was filtered off, washed thoroughly with water,and dried in vacuo; yield 23.85 g. ¹H-NMR (d₆-DMSO) δ 2.36 (2H, t), 3.47(2H, m), 4.57 (1H, m), 7.24 (1H, s), 12.2 & 12.4 (each 1H, br s); MS(APCI−). found (M−H)=171 C₆H₈N₂O₂S, requires 172.

Intermediate B111 Ethyl (2,4-dioxo-4H-benzo[d][1,3]oxazin-1-yl)acetate

Isatoic anhydride (10 g, 1 equiv) in dimethylformamide (30 ml) was addeddropwise to a suspension of sodium hydride (2.45 g, 60% in mineral oil,1 equiv) in dimethylformamide (70 ml) at room temperature. The reactionwas stirred for 1 hour prior to the addition of ethyl bromoacetate (6.8ml, 1 equiv) and the resulting mixture stirred for 16 hours. Solventevaporated, the residue suspended in water and the solid collected. Thetitle compound was obtained by crystallisation from ethyl acetate (10.5g). ¹H-NMR (CDCl₃), δ 1.29 (3H, t), 4.27 (2H, q), 4.82 (2H, s), 6.96(1H, d), 7.33 (1H, t), 7.74 (1H, dt), 8.19 (1H, dd).

Intermediate B112 Ethyl(4-oxo-2-thioxo-3,4-dihydro-2H-quinazolin-1-yl)acetate

Intermediate B111 (2.64 g, 1 equiv) and thiourea (2.42 g, 4 equiv) in1-methyl-2-pyrrolidinone (40ml) was heated to 180° C. for 2 hours. Aftercooling the mixture was treated with water and the resultant solidcollected by filitration. This solid was applied to a column (silica, 2%methanol/dichloromethane) to afford the title compound as a colourlesssolid (0.169 g). ¹H-NMR (CDCl₃) δ 1.22 (3H, t), 4.21 (2H, q), 5.53 (2H,br s), 7.46 (1H, t), 7.53 (1H, d), 7.81 (1H, dt), 8.07 (1H, dd).

Intermediate B113 Methyl3-[3-(1-phenylmethanoyl)thioureido]thiophene-2-carboxylate

Methyl-3-amino-2-thiophene carboxylate (30 g, 1 equiv) and benzoylisothiocyanate (46 ml, 1.8 equiv) in acetone (250 ml) were heated to 65°C. for 30 minutes. After cooling the solution was concentrated and theresulting solid filtered off and dried (40.54 g). ¹H-NMR (CDCl₃) δ 3.98(3H, s) 7.54 (4H, m), 7.94 (2H, m), 8.81 (1H, d), 9.15 (1H, br s); MS(APCI+). found (M+1)=321; C₁₄H₁₂N₂O₃S₂, requires 320.

Intermediate B114 2-Thioxo-2,3-dihydro-1H-thieno [3,2-d]pyrimidin-4-one

Potassium hydroxide (13.83 g, 2 equiv) was dissolved in ethanol (1000ml) and then poured onto intermediate B113 (40.54 g, 1 equiv) withstirring. The mixture was heated to relux for 1 hour and after coolingthe title compound was obtained by filitration (17.32 g). ¹H-MNR(CDCl₃), δ 6.87 (1H, d), 7.77 (1H, d), 10.46 (2H, br s); MS (APCI−).found (M−1)=183; C₆H₄N₂OS₂, requires 184.

The following intermediates were prepared by the method of IntermediateB10

No. Precursor Name B11 monoethyl succinate 5-carboxymethyl-2-thiouracilB12 ethyl ethoxyacetate 5-ethoxy-2-thiouracil B13ethyl(methylthio)acetate 5-methylthio-2-thiouracil

Intermediate B20 2-(4-fluorobenzylthio)-5-methylpyrimidin-4-one

A mixture of Intermediate B2 (9.45 g, 1 equiv), 4-fluorobenzyl chloride(7.96 ml, 1 equiv), potassium carbonate (18.4 g, 2 equiv) and dimethylformamide (100 ml) was stirred at 90° C. under argon for 16 h. The DMFwas removed in vacuo, water was added, and the product was extractedinto ethyl acetate. The organic layer was dried and evaporated, and theresidue was triturated with petroleum ether to obtain the title compoundas a white solid (8.76 g). ¹H-NMR (CDCl₃) δ 2.02(3H, s), 4.38 (2H, s),6.97 (2H, m), 7.35 (2h,m), 7.74 (1H, s); MS (APCI+). found (M+1)=251;C₁₂H₁₁FN₂OS, requires 250.

The following intermediates were prepared by the method of IntermediateB20:

No. Precursor Name B21 Int. B1 2-(4-fluorobenzylthio)pyrimidin-4-one B22Int. B3 2-(4-fluorobenzylthio)-5-ethylpyrimidin-4-one B23 Int. B42-(4-fluorobenzylthio)-5-propylpyrimidin-4-one B24 Int. B62-(4-fluorobenzylthio)-5- ethoxycarbonylpyrimidin-4-one B25 Int. B102-(4-fluorobenzylthio)-5-(2-hydroxyethyl)pyrimidin- 4-one B26 Int. B52-(4-fluorobenzylthio)-5,6-dimethylpyrimidin- 4-one B27 Int. B72-(4-fluorobenzylthio)-5,6- trimethylenepyrimidin-4-one B28 Int. B82-(4-fluorobenzylthio)-5,6- tetramethylenepyrimidin-4-one B29 Int. B92-(4-fluorobenzylthio)-5-methoxypyrimidin-4-one B30 Int. B122-(4-fluorobenzylthio)-5-ethoxypyrimidin-4-one B31 Int. B132-(4-fluorobenzylthio)-5-methylthiopyrimidin- 4-one B132 Int. B1142-(4-fluorobenzylthio)-1H-thieno[3,2- d]pyrimidin-4-one

The following intermediates were prepared by method of Intermediate B20and the appropriate benzyl chloride.

No. Precursor Name B133 Int. B7 2-(2,3-difluorobenzylthio)-5,6-2,3-difluorobenzyl chloride trimethylenepyrimidin-4-one B134 Int. B72-(3,4-difluorobenzylthio)-5,6- 3,4-difluorobenzyl chloridetrimethylenepyrimidin-4-one B135 Int. B72-(2,3,4-trifluorobenzylthio)-5,6- 2,3,4-trifluorobenzyl chloridetrimethylenepyrimidin-4-one B136 Int. B7 2-(2-fluorobenzylthio)-5,6-2-fluorobenzyl chloride trimethylenepyrimidin-4-one

Intermediate B37

2-(4-fluorobenzylthio)-5-hydroxymethylpyrimidin-4-one

Borane-tetrahydrofuran complex (143 ml, 2.2 equiv, 1.0M in THF) wasadded dropwise to an ice-cooled solution of Intermediate B24 (20 g, 1equiv) in dry THF (700 ml) under argon with stirring. After a further 30min at 0° C., the mixture was allowed to warm to room temperature andstirring continued overnight. The solvent was evaporated, 50% aqueousacetic acid (500 ml) was added with stirring, and the mixture wasevaporated to dryness. The residue was digested with hot water (500 ml)for 5 min, then the solid was filtered off. Both this solid and thefiltrate were extracted with dichloromethane, and the organic extractswere combined and purified by chromatography (silica, 2-8% methanol indichloromethane). Product fractions were evaporated to a white solid(6.14 g). ¹H-NMR (d₆-DMSO) δ 4.25 (2H, s), 4.39 (2H, s), 7.14 (2H, t),7.45 (2H, m), 7.82 (1H, br s); MS (APCI+). found (M+1)=267;C₁₂H₁₁FN₂O₂S, requires 266.

Intermediate B382-(4-fluorobenzylthio)-5-isopropoxycarbonylmethylpyrimidin-4-one

A mixture of Intermediate B11 (2.60 g, 1 equiv), 4-fluorobenzyl bromide(1.74 ml, 1 equiv) and 2-propanol (50 ml) was stirred at reflux for 3 h,then concentrated to a slurry in vacuo and diluted with ether. The solidwas filtered off, washed with ether and dried; yield 2.87 g. ¹H-NMR(d₆-DMSO) δ 1.17 (6H, d), 3.31 (2H, s), 4.40 (2H, s), 4.89 (1H, m), 7.14(2H, t), 7.45 (2H, m) 7.84 (1H, s); MS (APCI+). found (M+1)=325;C₁₅H₁₇FN₂O₃S, requires 324.

Intermediate B401-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-methylpyrimidin-4-one

A mixture of Intermediate B20 (6.30 g, 1 equiv), t-butyl iodoacetate(6.1 g, 1 equiv), diisopropyl-ethylamine (5.27 ml, 1.2 equiv) anddichloromethane (100 ml) was stirred at ambient temperature under argonfor 16 h, then the solution was washed with aq. ammonium chloride andaq. sodium bicarbonate, dried and evaporated. Chromatography (silica,ethyl acetate +0.5% v/v aq. ammonia) followed by crystallisation fromethyl acetate gave the title compound as a white solid (3.36 g). ¹H-NMR(CDCl₃) δ 1.44 (9H, s), 2.01 (3H, d), 4.36 (2H, s), 4.51 (2H, s), 6.98(3H, m), 7.36 (2H, m); MS (APCI+). found (m+1)=365; C₁₈H₂₁FN₂O₃S,requires 364.

The following intermediates were prepared by the method of IntermediateB40:

No. Precursor Name B41 Int. B21 1-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)pyrimidin-4-one B42 Int. B221-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-ethylpyrimidin-4-one B43 Int. B231-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-propylpyrimidin-4-one B44 Int. B241-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-ethoxycarbonyl-pyrimidin-4-one B45 Int. B381-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-isopropoxycarbonylmethylpyrimidin-4-one B46 Int. B371-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-hydroxymethyl-pyrimidin-4-one B47 Int. B251-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-(2-hydroxyethyl)pyrimidin-4-one B48 Int. B261-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5,6-dimethyl-pyrimidin-4-one B49 Int. B271-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5,6-trimethylene-pyrimidin-4-one B50 Int. B281-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5,6-tetramethylene-pyrimidin-4-one B51 Int. B291-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-methoxy-pyrimidin-4-one B52 Int. B301-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-ethoxypyrimidin-4-one B53 Int. B311-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-methylthio-pyrimidin-4-one B154 Int. B1331-(tert-Butoxycarbonylmethyl)-2-(2,3-difluorobenzylthio)-5,6-tetramethylenepyrimidin-4-one B155 Int. B1341-(tert-Butoxycarbonylmethyl)-2-(3,4-difluorobenzylthio)-5,6-tetramethylenepyrimidin-4-one B156 Int. B1351-(tert-Butoxycarbonylmethyl)-2-(2,3,4-trifluorobenzylthio)-5,6-tetramethylenepyrimidin- 4-one B157 Int. B1361-(tert-Butoxycarbonylmethyl)-2-(2-fluorobenzylthio)-5,6-tetramethylene-pyrimidin-4-one B158 Int. B1321-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-4-oxo-4H-thieno[3,2-d]pyrimidin-1-one

The following intermediate was prepared by the method of IntermediateB20:

No. Precursor Name B159 B112Ethyl[2-(4-fluorobenzylthio)-4-oxo-4H-quinazolin- 1-yl]acetate

Intermediate B561-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-chloropyrimidin-4-one

A mixture of Intermediate B41 (7.45 g, 1 equiv), N-chlorosuccinimide(2.84 g, 1 equiv) and carbon tetrachloride (150 ml) was stirred atreflux under argon for 2 h, then the solution was evaporated.Chromatography (silica, ethyl acetate) followed by trituration withether gave the title compound as a white solid (4.45 g). ¹H-NMR (CDCl₃)δ 1.45 (9H, s), 4.40 (2H, s), 4.50 (2H, s), 6.99 (2H, m) 7.35 (2H, m),7.40 (1H, s); MS (APCI+). found (M+1)=385/387; C₁₇H₁₈ClFN₂O₃S, requires384/386.

Intermediate B571-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-bromopyrimidin-4-one

Prepared as Intermediate B56, but using N-bromosuccinimide in place ofN-chlorosuccinimide. ¹H-NMR (CDCl₃), δ 1.45 (9H, s), 4.40 (2H, s), 4.49(2H, s), 6.99 (2H, m), 7.35 (2H, m) 7.53 (1H, s); MS (APCI+). found(M+1)=429/431; C₁₇H₁₈BrFN₂O₃S, requires 428/430.

Intermediate B581-(tert-Butoxycarbonylmethyl)-2-(4-fluorobenzylthio)-5-methylsulfinyl-pyrimidin-4-one

m-Chloroperbenzoic acid (0.93 g) was added to an ice-cooled slurry ofIntermediate B53 (1.50 g) in dichloromethane (20 ml). The resultingsolution was allowed to warm to room temperature and stirred for 30 min,then washed with aq. sodium bicarbonate. Chromatography (silica, 3-8%methanol in ethyl acetate) gave the title compound as a white solid(1.15 g). ¹H-NMR (CDCl₃) δ 1.46 (9H, s), 2.94 (3H, s), 4.51 (4H, m),7.01 (2H, m), 7.37 (2H, m), 7.60 (1H, s); MS (APCI+). found (M+1)=413;C₁₈H₂₁FN₂O₄s₂, requires 412.

Intermediate B601-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-methylpyrimidin-4-one

Intermediate B40 (3.88 g) was added to solution of trifluoroacetic acid(10 ml) in dichloromethane (20 ml) under argon, and stirred overnight atroom temperature. Evaporation of the solvent and trituration with ethergave the title compound as a white solid (3.04 g). ¹H-NMR (d₆-DMSO) δ1.81 (3H, d), 4.42 (2H, s), 4.66 (2H, s), 7.14 (2H, m), 7.47 (2H, m),7.63 (1H, m); MS (APCI+1). found (M+1)=309; C₁₄H₁₃FN₂O₃S, requires 308.

The following intermediates were prepared by the method of IntermediateB60:

No. Precursor Structure Name B61 Int. B41

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-pyrimidin-4-one B62 Int. B42

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-ethylpyrimidin-4-one B63 Int.B43

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-propylpyrimidin-4-one B64Int. B44

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-ethoxycarbonylpyrimidin-4-oneB65 Int. B45

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-isopropoxycarbonylmethylpyrimidin-4-oneB66 Int. B46

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-hydroxymethylpyrimidin-4-oneB67 Int. B47

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-(2-hydroxyethyl)pyrimidin-4-oneB68 Int. B48

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5,6-dimethylpyrimidin-4-one B69Int. B49

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5,6-trimethylenepyrimidin-4-oneB70 Int. B50

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5,6-tetramethylenepyrimidin-4-oneB71 Int. B56

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-chloropyrimidin-4-one B72Int. B57

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-bromopyrimidin-4-one B73 Int.B51

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-methoxypyrimidin-4-one B74Int. B52

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-ethoxypyrimidin-4-one B75Int. B53

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-methylthiopyrimidin-4-one B76Int. B58

1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-methylsulfinylpyrimidin-4-oneB177 Int. B154

1-(Carboxymethyl)-2-(2,3-difluorobenzylthio)-5,6-trimethylenepyrimidin-4-oneB178 Int. B155

1-(Carboxymethyl)-2-(3,4-difluorobenzylthio)-5,6-trimethylenepyrimidin-4-oneB179 Int. B156

1-(Carboxymethyl)-2-(2,3,4-trifluorobenzylthio)-5,6-trimethylenepyrimidin-4-oneB180 Int. B157

1-(Carboxymethyl)-2-(2-fluorobenzylthio)-5,6-trimethylenepyrimidin-4-oneB181 Int. B158

[2-(4-Fluorobenzylthio)-4-oxo-4 H-thieno[3,2-d]pyrimidin-1-yl]aceticacid B182 Int. B159

[2-(4-Fluorobenzylthio)-4-oxo-4 H-quinazolin-1-yl]acetic acid

Intermediate B801-(N-Methyl-N-(4-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-azidoethyl)pyrimidin-4-one

A mixture of Example 39 (1.88 g, 1 equiv), methanesulfonic anhydride(0.713 g, 1.2 equiv), triethylamine (0.665 ml) and dichloromethane (20ml) was stirred at 0° C. for 4 h. The solution was washed with water,dried and evaporated to a pale foam (2.4 g). This was dissolved indimethylformamide (20 ml), sodium azide (0.266 g, 1.2 equiv) was added,and the mixture was stirred under argon at room temperature overnight.The solvent was evaporated, the residue was partitioned between waterand dichloromethane, and the organic layer was dried and evaporated.Chromatography (silica, ethyl acetate) gave the title compound as awhite solid. ¹H-NMR (CDCl₃) δ 2.66 (2H, m), 2.88 (3H, s), 3.60 (2H, m),4.46-4.64 (6H, m), 6.84-7.50 (12H, m), 8.02 (1H, s); MS (APCI+). found(M+1)=577/579 C₂₉H₂₆ClFN₆O₂S, requires 576/578.

The following compound was prepared by the method of Intermediate B80

No. Precursor Name B81 Example 1-(N-(2-(Diethylamino)ethyl)-N-(4-(4- 42trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2- azidoethyl)pyrimidin-4-one

Example 11-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-ethylpyrimidin-4-onebitartrate

A mixture of Intermediate A30 (0.403 g, 1 equiv), Intermediate B62(0.371 g, 1 equiv), HATU (0.426 g, 1.2 equiv), di-isopropylethylamine(0.482 ml, 2.4 equiv) and dichloromethane (15 ml) was stirred at roomtemperature overnight, then washed with aqueous ammonium chloride andaqueous sodium bicarbonate. The organic layer was dried and evaporated,and the product purified by chromatography (silica, 5% methanol indichloromethane). Product fractions were evaporated to a white foam(0.627 g). This free base (0.612 g) was dissolved in methanol (10 ml),tartaric acid (0.14 g) was added, the mixture was stirred for 5 minsthen evaporated. Trituration with ether gave the bitartrate salt as awhite solid (0.622 g). ¹H-NMR (d₆-DMSO, ca 1:1 rotamer mixture) δ 0.96(3H, m), 1.07 (6H, m), 2.27 (2H, m), 2.59 (2H, m), 2.84 (2H, m),3.37/3.50 (4H, m), 4.26 (2H, s), 4.39/4.43 (2H, 2×s), 4.64/4.72 (2H,2×s), 4.94/5.09 (2H, 2×s), 7.11/7.14 (2H, 2×m), 7.36-7.49 (5H, m),7.63/7.72 (2H, 2×d), 7.84 (4H, m); MS (APCI+). found (M+1)=655;C₃₅H₃₈F₄N₄O₂S, requires 654.

Example 21-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-ethylpyrimidin-4-onebitartrate

Prepared from intermediates A31 and B62 by the method of Example 1.¹H-NMR (d₆-DMSO, ca 2:1 rotamer mixture) δ 0.93 (6H, m), 1.08 (3H, m),2.27 (2H, m), 2.66 (4H, m), 3.39/3.45 (4H, m), 4.21 (2H, s), 4.39/4.42(2H, 2×s), 4.66/4.77 (2H, 2×s), 4.97/5.10 (2H, 2×s), 7.09/7.12 (2H,2×t), 7.42/7.49 (2H, 2×t), 7.79/7.86 (1H, 2×dd), 7.87 (2H, d), 7.97/8.06(1H, 2×dd), 8.28 (2H, d), 8.62/8.71 (2H, 2×s); MS (APCI+). found(M+1)=656; C₃₄H₃₇F₄N₅O₂S, requires 655.

Example 3(a)1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-one

Intermediate B69 (87.1 g, 0.26 mol.) was suspended in dichloromethane(2.9 liter). 1-Hydroxybenzotriazole hydrate (35.2 g, 0.26 mol.) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99.7 g,0.52 mol.) were added and the suspension stirred for 45 minutes by whichtime complete solution had been obtained. Intermediate A30 (91.2 g, 0.26mol.) was added as a solution in dichloromethane (100 ml) over 5 minutesand the solution stirred for 4 hours. Saturated ammonium chloridesolution:water mixture (1:1, 1 liter) was added and the solution stirredfor 10 minutes. The organic phase was separated and extracted withsaturated with ammonium chloride:water mixture (1:1, 1 liter), extractswere pH 6. The organic phase was separated and extracted with water (1liter) containing acetic acid (10 ml), extract pH 5. The dichloromethanelayer was separated and extracted with saturated sodium carbonatesolution:water:saturated brine mixture (1:3:0.2, 1 liter), pH 10.5, thenwith saturated brine:water mixture (1:1, 1 liter). The brown solutionwas dried over anhydrous sodium sulfate in the presence of decolourisingcharcoal (35 g), filtered and the solvent removed in vacuo to give adark brown foam. The foam was dissolved in iso-propyl acetate (100 ml)and the solvent removed in vacuo. The dark brown gummy residue wasdissolved in boiling iso-propyl acetate (500 ml), cooled to roomtemperature, seeded and stirred overnight. The pale cream solid producedwas filtered off and washed with iso-propyl acetate (100 ml). The solidwas sucked dry in the sinter for 1 hour then recrystallized fromiso-propyl acetate (400 ml). After stirring overnight the solid formedwas filtered off and washed with iso-propyl acetate (80 ml) and dried invacuo to give the title compound, 110 g, 63.5% yield. 1H NMR (CDCl₃, ca1.9:1 rotamer mixture) δ 0.99 (6H, t), 2.10 (2H, m), 2.50 (4H, q),2.58/2.62 (2H, 2 ×t), 2.70/2.82 (2H, 2 ×t), 2.86 (2H, t), 3.28/3.58 (2H,2 ×t), 4.45/4.52 (2H, 2 ×s), 4.68/4.70 (2H, 2 ×s), 4.93 (2H, s) 6.95(2H, m), 7.31 (2H, d), 7.31/7.37 (2H, 2 ×m), 7.48/7.52 (2H, d), 7.65(2H, m), 7.72 (2H, m); MS (APCI) (M+H)⁺ 667; mp 125° C. (byDSC—assymetric endotherm).

Example 3(b)1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate

Prepared from intermediates A30 and B69 by the method of Example 1.¹H-NMR (d₆-DMSO, ca 1:1 rotamer mixture) δ 0.92/0.99 (6H, 2×t), 1.99(2H, m), 2.54 (6H, m), 2.68/2.74 (4H, m), 3.36 (2H, m), 4.21 (2H, s),4.37/4.44 (2H, 2×s), 4.63/4.74 (2H, 2×s), 4.89/5.13 (2H, 2×s), 7.08/7.14(2H, 2×m), 7.36-7.50 (4H, m), 7.64/7.70 (2H, 2×d), 7.83 (4H, m); MS(APCI+). found (M+1)=667; C₃₆H₃₈F₄N₄O₂S, requires 666.

Example 3(c)1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onehydrochloride

The free base from Example 3(a) (3.00 g, 0.0045 mol) was suspended withstirring in isopropanol (30 ml) and warmed to 45° C. to give a clearsolution. The solution was then cooled to ambient temperature and conc.hydrochloric acid (0.40 ml, 0.045 mol) was added. The resultant slurrywas then stirred at ambient temperature for 35 minutes, before beingcooled to 0° C. for 35 minutes. The slurry was then filtered and washedwith isopropyl (10 ml), followed by heptane (30 ml), before being driedunder vacuum to give the title compound as a white solid (3.00 g, 95%).¹H NMR (CDCl₃) δ 1.38 (6H, t), 2.08 (2H, m) 282 (2H, t), 2.99 (2H, t),3.19 (4H, m), 3.35 (2H, m), 3.97 (2H, s), 4.42 (2H, s), 4.81 (2H, s)4.99 (2H, s), 6.87 (2H, t), 7.26 (2H, t), 7.33 (2H, d), 7.41 (2H, d),7.53 (2H, d), 7.71 (2H, d), 11.91 (1H, s).

Example 41-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate

Prepared from intermediates A31 and B69 by the method of Example 1. ¹H-NMR (d₆-DMSO, ca 3:1 rotamer mixture) δ 0.92/0.98 (6H, t), 1.99 (2H,m), 2.53 (6H, m), 2.68/2.75 (4H, m), 3.41 (2H, m) 4.22 (2H, s),4.37/4.42 (2H, 2×s), 4.66/4.79 (2H, 2×s), 4.93/5.13 (2H, 2×s), 7.07/7.12(2H, 2×t), 7.39/7.47 (2H, 2×t), 7.77/7.86 (1H, 2×dd), 7.87 (2H, d),7.98/8.05 (1H, 2×dd), 8.28 (2H, d), 8.61/8.69 (1H, 2×s); MS (APCI+).found (M+1)=668; C₃₅H₃₇F₄N₅O₂S requires 667.

Example 51-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrimid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate

Prepared from intermediates A33 and B69 by the method of Example 1.¹H-NMR (d₆-DMSO, ca 3:1 rotamer mixture) δ 0.92/1.09 (6H, t), 1.96 (2H,m), 2.60 (6H, m), 2.75 (4H, m), 3.48 (2H, m), 4.23 (2H, s), 4.38/4.40(2H, 2×s), 4.65/4.81 (2H, 2×s), 4,97/5.11 (2H, 2×s), 7.07/7.10 (2H,2×t), 7.38/7.44 (2H, 2×t), 7.91 (2H, d), 8.57 (2H, d), 8.84/8.93 (2H,2×s); MS (APCI+). found (M+1)=669; C₃₄H₃₆F₄N₆O₂S, requires 668.

Example 61-(N-Methyl-N-(2-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(2-aminoethyl)pyrimidin-4-onehydrochloride

A solution of Intermediate B80 (0.228 g) in ethanol (20 ml) washydrogenated over 10% palladium on charcoal (0.09 g) at atmosphericpressure for 2 days. The catalyst was filtered off, the solvent wasremoved in vacuo, and the resulting oil was purified by chromatography(silica, 10% methanolic ammonia in dichloromethane). The free base wasdissolved in dichloromethane (5 ml), and an equimolar quantity ofhydrogen chloride in ether added. The solvent was removed in vacuo, andthe residue triturated with ether; yield 0.132 g). ¹H-NMR (d₆-DMSO, ca2:1 rotamer mixture) δ 2.58 (2H, m), 2.87/2.99 (3H, 2×s), 2.99 (2H, m),4.40/4.45 (2H, 2×s), 4.57/4.66 (2H, 2×s), 4.97/5.00 (2H, 2×s), 7.16 (2H,m), 7.33/7.38 (2H, 2×d), 7.4-7.7 (9H, m), 8.0 (2H, br m); MS (APCI+).found (M+1)=551/553; C₂₉H₂₈ClFN₄O₂S, requires 550/552.

Example 71-(N-Methyl-N-(2-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-(2-acetamidoethyl)pyrimidin-4-one

A solution of Example 6 (0.173 g, 1 equiv), acetic anhydride (0.033 ml,1.1 equiv) and diisopropylamine (0.066 ml, 1.2 equiv) in dichloromethane(10 ml) was stirred at room temperature overnight. The solution waswashed with aq. ammonium chloride and aq. sodium bicarbonate, then theorganic layer was dried and evaporated. The residue was triturated withether to obtain the title compound as a white solid (0.156 g). ¹H-NMR(CDCl₃, ca 2:1 rotamer mixture) δ 1.96 (3H, s), 2.64 (2H, m), 2.96/3.10(3H, 2×s), 3.49 (2H, m), 4.46-4.64 (6H, m), 6.77 (1H, br t), 6.97-7.16(3H, m), 7.26-7.49 (10H, m); MS (APCI+). found (M+1)=593/595;C₃₁H₃₀ClFN₄O₃S, requires 592/594.

Example 81-(N-(2-(Diethylamino)ethyl)-N-(2-(4-chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(dimethylaminomethyl)pyrimidin-4-one

Methanesulfonic anhydride (0.134 g, 1.2 equiv) was added to a solutionof Example 37 (0.40 g, 1 equiv) and triethylamine (0.124 ml, 1.4 equiv)in dichloromethane (5 ml) at 0° C., then stirred at this temperature for4 hours. The mixture was washed with water, dried and evaporated toyield the mesylate as a pale yellow solid. This was dissolved in a 2Msolution of dimethylamine in THF (10 ml) and stirred at room temperaturefor 16 hours. The solvent and excess dimethylamine was removed in vacuo,and the product was purified by chromatography (silica, 5-20% methanolin ethyl acetate, then 1-10% mehtanolic ammonia in dichloromethane) toobtain the title compound. ¹H-NMR (CDCl₃) δ 0.98 (6H, t), 2.28/2.30(each 3H, s), 2.46-2.65 (6H, m), 3.26/3.56 (2H, 2×t), 3.33/3.36 (2H,2×s), 4.46/4.53/5.54/4.90 (4H, 4 ×s), 4.67 (2H, s), 6.98 (2H, m),7.21-7.50 (11H, m); MS (APCI+). found (M+1)=650/652; C₃₅H₄₁CIFN₅O₂S,requires 649/651.

The following Examples were made by the method of Example 1 except thatin a few cases EDC (2 equiv) and 1-hydroxybenzotriazole (1 equiv) wereused in place of HATU and di-isopropylamine, in an essentially similarprocedure. Where indicated, the salts were subsequently prepared by themethods of Examples 1 or 6 as appropriate:

Ex. No. Precursors Structure Name 20 Int. A3Int. B60

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-methyl-pyrimidin-4-onehydrochloride 21 Int. A26Int. B60

1-(N-methyl-N-(2-(4-trifluoromethyl-phenyl)pyrid-5-ylmethyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-methyl-pyrimidin-4-onebitartrate 22 Int. A30Int. B60

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-methylpyrimidin-4-onebitartrate 23 Int. A31Int. B60

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-yl-methyl)-aminocarbonyl-methyl)-2-(4-fluoro-benzyl)thio-5-methylpyrimidin-4-onebitartrate24 Int. A32Int. B60

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-chlorophenyl)pyrimid-5-yl-methyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-methylpyrimidin-4-onebitartrate 25 Int. A33Int. B60

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrimid-5-yl-methyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-methylpyrimidin-4-onebitartrate 26 Int. A35Int. B60

(±)-1-(N-(2-(Diethylamino)ethyl)-N-(1-(4-(4-chlorophenyl)phenyl)ethyl)-amino-carbonyl-methyl)-2-(4-fluorobenzyl)thio-5-methylpyrimidin-4-onebitartrate 27 Int. A34Int. B60

1-(N-(2-(1-piperidino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-amino-carbonyl-methyl)-2-(4-fluorobenzyl)thio-5-methylpyrimidin-4-one bitartrate 28 Int. A25Int. B62

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-ethylpyrimidin-4-one29 Int. A3Int. B62

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-ethyl-pyrimidin-4-onebitartrate 30 Int. A26Int. B62

1-(N-methyl-N-(2-(4-trifluoromethyl-phenyl)pyrid-5-yl-methyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-ethyl-pyrimidin-4-one31 Int. A32Int. B62

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-chlorophenyl)pyrimid-5-yl-methyl)-amino-carbonyl-methyl)-2-(4-fluorobenzyl)thio-5-ethylpyrimidin-4-onebitartrate 32 Int. A33Int. B62

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrimid-5-yl-methyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-ethylpyrimidin-4-onebitartrate33 Int. A3Int. B63

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-propylpyrimidin-4-onebitartrate 34 Int. A30Int. B63

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-amino-carbonyl-methyl)-2-(4-fluorobenzyl)thio-5-propylpyrimidin-4-onebitartrate 35 Int. A30Int. B64

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-ethoxycarbonylmethylpyrimidin-4-onebitartrate36 Int. A30Int. B65

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-isopropoxycarbonylmethylpyrimidin-4-onebitartrate 37 Int. A3Int. B66

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-hydroxy-methylpyrimidin-4-onebitartrate38 Int. A30Int. B66

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-amino-carbonyl-methyl)-2-(4-fluorobenzyl)thio-5-hydroxymethylpyrimidin-4-onebitartrate39 Int. A2Int. B67

1-(N-methyl-N-(4-(4-chlorophenyl)-benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(2-hydroxyethyl)-pyrimidin-4-onebitartrate 40 Int. A3Int. B67

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(2-hydroxyethyl)pyrimidin-4-onebitartrate 41 Int. A31Int. B67

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-yl-methyl)-aminocarbonyl-methyl)-2-(4-fluoro-benzyl)thio-5-(2-hydroxyethyl)pyrimidin-4-onebitartrate 42 Int. A30Int. B67

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(2-hydroxyethyl)pyrimidin-4-onebitartrate43 Int. A30Int. B68

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonyl-methyl)-2-(4-fluorobenzyl)thio-5,6-dimethylpyrimidin-4-onebitartrate 44 Int. A3Int. B69

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate 45 Int. A3Int. B70

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5,6-tetramethylenepyrimidin-4-onebitartrate 46 Int. A30Int. B70

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-tetramethylenepyrimidin-4-onebitartrate47 Int. A31Int. B70

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-yl-methyl)-aminocarbonylmethyl)-2-(4-fluorobenzyl)-thio-5,6-tetramethy-lenepyrimidin-4-onebitartrate 49 Int. A30Int. B71

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonyl-methyl)-2-(4-fluorobenzyl)thio-5-chloropyrimidin-4-onebitartrate 50 Int. A3Int. B71

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-chloro-pyrimidin-4-onebitartrate 51 Int. A31Int. B71

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-yl-methyl)-aminocarbonyl-methyl)-2-(4-fluoro-benzyl)thio-5-chloropyrimidin-4-onebitartrate52 Int. A30Int. B72

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonyl-methyl)-2-(4-fluorobenzyl)thio-5-bromopyrimidin-4-onebitartrate 53 Int. A3Int. B72

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)-aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-bromo-pyrimidin-4-onebitartrate 54 Int. A30Int. B73

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-methoxypyrimidin-4-one-bitartrate55 Int. A31Int. B73

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-yl-methyl)-aminocarbonylmethyl)-2-(4-fluorobenzyl)-thio-5-methoxypyrimidin-4-onebitartrate 56 Int. A30Int. B74

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-ethoxypyrimidin-4-onebitartrate 57 Int. A31Int. B74

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-yl-methyl)-aminocarbonylmethyl)-2-(4-fluorobenzyl)-thio-5-ethoxypyrimidin-4-onebitartrate 58 Int. A31Int. B75

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-yl-methyl)-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5-methylthiopyrimidin-4-onebitartrate 59 Int. A30Int. B75

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-methylthiopyrimidin-4-onebitartrate 60 Int. A30Int. B76

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluoro-benzyl)thio-5-methylsulfinyl-pyrimidin-4-onebitartrate 61 Int. A31Int. B76

1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-yl-methyl)-aminocarbonylmethyl)-2-(4-fluorobenzyl)-thio-5-methylsulfinyl-pyrimidin-4-onebitartrate 62 Int. A30Int. B177

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(2,3-difluorobenzyl)-thio-5,6-trimethylenepyrimidin-4-onebitartrate63 Int. A30Int. B178

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(3,4-difluorobenzyl)-thio-5,6-trimethylenepyrimidin-4-onebitartrate64 Int. A30Int. B179

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(2,3,4-trifluorobenzyl)-thio-5,6-trimethylenepyrimidin-4-onebitartrate 65 Int. A30Int. B180

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(2-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate66 Int. A25Int. B69

1-(N-methyl-N-(4-(4-trifluoromethyl-phenyl)benzyl)-aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylene-pyrimidin-4-one67 Int. A34Int. B69

1-(N-(2-(1-piperidino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate68 Int. A36Int. B69

1-(N-(2-(Diethylamino)ethyl)-N-(3-(4-trifluoromethylphenoxy)benzyl)-aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylene-pyrimidin-4-one69 Int. A37Int B69

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenoxy)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate70 Int. A39Int. B69

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethyl-biphenyl-4-yl)propyl)-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5,6-trimethylenepyrimidin-4-one71 Int. A39Int. B62

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethyl-biphenyl-4-yl)propyl)-aminocarbonyl-methyl)-2-(4-fluoro-benzyl)thio-5-ethylpyrimidin-4-one72 Int. A140Int. B62

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethyl-biphenyl-4-yloxy)ethyl)-aminocarbonyl-methyl)-2-(4-fluoro-benzyl)thio-5-ethylpyrimidin-4-one73 Int. A18Int. B69

1-(N-(1-Ethyl-piperidin-4-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate74 Int A141Int. B69

1-(N-(2-Ethylamino-2-methylpropyl)-N-(4-(4-trifluoromethylphenyl)benzyl)a-mino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylene-pyrimidin-4-onebitartrate 75 Int. A142Int. B69

N-(2-tert-butylaminoethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate76 Int. A30Int. B181

N-(2-Diethylaminoethyl)-2-[2-(4-fluoro-benzylthio)-4-oxo-4H-thieno[3,2-d]pyrimidin-1-yl]-N-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-acetamidebitartrate77 Int. A30Int. B182

N-(2-Diethylaminoethyl)-2-[2-(4-fluoro-benzylthio)-4-oxo-4H-quinazolin-1-yl]-N-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-acetamidebitartrate 78 Int. A38Int. B69

Ethyl-{2-[{2-(4-fluorobenzylthio)-4-oxo-4,5,6,7-tetrahydrocyclopentapyrimidin-1-yl]-ethanoyl}-{4′-trifluoromethyl-biphenyl-4-ylmethyl)-amino]-ethyl}carbamicacid tert-butyl ester 79 Int. A60Int. B69

1-(N-(1-Methylpiperidin-4-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate80 Int. A61Int. B69

1-(N-(1-Isopropylpiperidin-4-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate81 Int. A62Int. B69

1-(N-(1-(2-Methoxyethyl)piperidin-4-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)-aminocarbonylmethyl)-2-(4-fluoro-benzyl)thio-5,6-trimethylenepyrimidin-4-onebitartrate

The following compound was prepared by the method of Example 6:

No. Precursor Structure Name 85 Int. B81

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-aminoethyl)pyrimidin-4-onebitartrate

The following compounds were prepared by the method of Example 7:

No. Precursors Structure Name 90 Example 85,aceticanhydride

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-acetamidoethyl)pyrimidin-4-onebitartrate91 Example 85,methane-sulfonicanhydride

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methanesulfonamidoethyl)pyrimidin-4-onebitartrate 92 Example 85,methoxy-acetylchloride

1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)amino-carbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-(methoxyacetamido)ethyl)pyrimidin-4-onebitartrate

The following example was prepared by the method of Intermediate B60.The salt was prepared by the method of example 1:

No. Precursor Structure Name 93 Exam 78

1-(N-(2-(Ethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)-aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylene-pyrimidin-4-onebitartrateBiological Data

1. Screen for Lp-PLA₂ Inhibition.

Enzyme activity was determined by measuring the rate of turnover of theartificial substrate (A) at 37 C in 50 mM HEPES(N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid) buffer containing150 mM NaCl, pH 7.4.

Assays were performed in 96 well titre plates.

Recombinant Lp-PLA₂ was purified to homogeneity from baculovirusinfected Sf9 cells, using a zinc chelating column, blue sepharoseaffinity chromatography and an anion exchange column. Followingpurification and ultrafiltration, the enzyme was stored at 6mg/ml at 4°C. Assay plates of compound or vehicle plus buffer were set up usingautomated robotics to a volume of 170 μl. The reaction was initiated bythe addition of 20 μl of 10× substrate (A) to give a final substrateconcentration of 20 μM and 10 μl of diluted enzyme to a final 0.2 nMLp-PLA₂.The reaction was followed at 405 nm and 37° C. for 20 minutes using aplate reader with automatic mixing. The rate of reaction was measured asthe rate of change of absorbance.

Results

The compounds described in the Examples were tested as described aboveand had IC₅₀ values in the range <0.1 nM to 10 μM.

1. A method of treating atherosclerosis comprising administering to apatient in need thereof a therapeutically effective amount of a compoundwhich is1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-one,or a pharmaceutically acceptable salt thereof.
 2. The method accordingto claim 1, wherein the compound is in the form of the free base.
 3. Themethod according to claim 1 wherein the compounds is1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-one,bitartrate or1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-onehydrochloride.
 4. The method according to claim 1 further comprisingco-administering a therapeutically effective amount of a cholesterollowering agent.
 5. The method according to claim 4, further comprisingco-administering a therapeutically effective amount of a statin.
 6. Themethod according to claim 5 wherein the statin is atorvastatin,simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin orZD4522.